This invention relates to novel 4-phenylpiperidines having utility in the treatment of pruritic dermatoses including allergic dermatitis and atopy in animals and humans, and processes for the preparation of and intermediates used in the preparation of such compounds.
Itching or pruritus is a common dermatological symptom which can give rise to considerable distress, in both humans and animals. Pruritus is often associated with inflammatory skin disease which can commonly be caused by hypersensitivity reactions, such as reaction to insect bites e.g. flea bites, or to environmental allergens such as house dust mite or pollen; or by bacterial and fungal infections of the skin or ectoparasite infections. Previous treatments for pruritus include the use of corticosteroids and antihistamines, however both have undesired side effects. Other therapies include the use of essential fatty acid dietary supplements which are slow to act and offer only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed but with limited success and there is a continuing need for an effective remedy.
Certain 1,3,4-trisubstituted 4-aryl-piperidine derivatives are disclosed in GB-A-1525584 as potent narcotic antagonists which also display analgesic properties. These compounds are also claimed in EP-B-0287339 as opioid antagonists which block the effect of agonists at the mu or kappa receptors having potential utility in treating a variety of disorders associated with these receptors such as eating disorders, opiate overdose, depression, smoking, alcoholism, sexual dysfunction, shock, stroke, spinal damage and head trauma; utility as an appetite suppressant for weight loss has also been suggested. Further related 1-N-substituted-4-aryl piperidines are disclosed in EP-A-0506468 and EP-A-0506478. Potential utility is suggested in preventing peripherally mediated undesired opiate effects and in relieving the symptoms of idiopathic constipation and irritable bowel syndrome.
According to the present invention we provide novel 4-phenylpiperidines which are potent and effective antipruritic agents.
Thus the present invention provides compounds having the formula: 
and pharmaceutically and veterinarily acceptable salts thereof wherein:
R1 and R2 are each independently H or C1-C4 alkyl; R3 is C1-C10 alkyl, C3-C10 alkenyl, or C3-C10 alkynyl; wherein said alkyl, alkenyl or alkynyl group may optionally be substituted by one or more substituents independently chosen from:
OH; CN; one or more halo atoms; C1-C6 alkoxy; C1-C6 alkoxycarbonyl; C2-C6 alkanoyl; C2-C6 alkanoyloxy; C3-C8 cycloalkyl; C3-C8 cycloalkoxy; C4-C9 cycloalkanoyl; aryl; aryloxy; aryl(C1-C4)alkoxy; heteroaryl; a saturated heterocyclic group; adamantyl or ZBNR4R5 wherein Z is a direct bond, CO or S(O)p wherein p=0, 1, 2 and wherein B=(CH2)m wherein m=from 0 to 10 and wherein R4 and R5 are independently selected from H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, aryl or heteroaryl or wherein R4 and R5 represent unbranched C2-C6 alkylene groups which when taken together with the N to which they are bonded form a 4 to 7 membered saturated heterocyclic ring optionally containing O, S or Nxe2x80x94R6 wherein said heterocyclic ring may be substituted by one or more C1-C4 alkyl groups and wherein R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, xe2x80x94(C1-C6 alkylene)(C3-C8 cycloalkyl) or xe2x80x94(C1-C6 alkylene)aryl and wherein when Z is a direct bond and m=0, then R3 is not a terminal alkenyl or alkynyl;
W is SO2, Cxe2x95x90O, P(Y1)xe2x95x90O or P(Y1)xe2x95x90S;
X is one or more substitutents independently selected from H, halo, C1-C4 alkyl, C1-C4 alkoxy, halo (C1-C4) alkyl or halo(C1-C4)alkoxy;
Y1 is C1-C10 alkyl which may optionally be substituted by one or more halo atoms or by OH, C1-C4 alkoxy, C2-C6 alkanoyloxy, CONH2, NH2 or aryl; NH2, mono or di-(C1-C4) alkylamino, C3-C8 cycloalkyl, aryl, phthalimidyl or heteroaryl;
Y2 is H, C1-C4 alkyl, or C3-C6 alkenyl, wherein said alkyl or alkenyl groups may optionally be substituted by aryl, aryloxy or heteroaryl;
n is 0, 1 or 2; and
y is 0 or 1.
In the definitions above, alkyl, alkenyl and alkynyl groups may be straight or branched-chain and halo means fluoro, chloro, bromo or iodo. The terms haloalkyl and haloalkoxy mean substituted by one or more halo atoms. Aryl and aryloxy means a phenyl, naphthyl, phenoxy or naphthyloxy group respectively which may optionally be substituted with from one to three substituents, each independently selected from OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C5 alkanoyl, halo, CN, CH2CN, and CONH2.
By heteroaryl is meant a 5 or 6 membered aromatic heterocyclic group containing as heteroatom one or more oxygen, sulphur or nitrogen atoms, and which may optionally be fused to a benzene ring and which may optionally be substituted in the heteroaryl or fused benzene ring with one or more substituents independently chosen from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, OH, xe2x95x90O, halo, aryl wherein aryl is preferably phenyl and CN. Particular examples of heteroaryl groups include pyrrolyl, imidazolyl, isoxazolyl, tetrazolyl, pyridyl, indolyl, benzofuranyl and quinolinyl, each optionally substituted as defined above.
By saturated heterocyclic groups is meant a 3 to 8 membered saturated heterocyclic group which contains as heteroatoms one or more oxygen, sulphur or nitrogen atoms, wherein the nitrogen atoms may optionally be substituted by C1-C4 alkyl and wherein the ring may optionally be benzo-fused. Particular examples include tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, N-methyl-piperidinyl, piperazinyl, morpholinyl and 2,3-dihydro-1-benzofuranyl.
The piperidines of this invention form pharmaceutically or veterinarily acceptable acid addition salts with a wide variety of inorganic and organic acids. The particular acid used in salt formation is not critical; however, the corresponding salt that is formed must be substantially non-toxic to animals. Typical acids generally used include sulfuric, hydrochloric, hydrobromic, phosphoric, hydroiodic, sulfamic, citric, acetic, maleic, malic, succinic, tartaric, cinamic, benzoic, ascorbic and related acids. The piperidines additionally form quaternary ammonium salts, for example, with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids, such as, for example camphorsulfonic acid.
The compounds of the invention contain one or more asymmetric centres and thus they can exist as enantiomers and diasteromers. The invention includes the use of both the separated individual isomers as well as mixtures of isomers.
Preferred herein are compounds wherein N(Y2)(WY1) is in the meta position, y is zero, W=SO2, R1 and R2 are C1-C4 alkyl groups with trans relative stereochemistry, preferably methyl groups, as detailed in the relative configuration illustrated by the general formula (Ia): 
or compounds wherein N(Y2)(WY1) is in the meta position, W=SO2, R1 is propyl and R2 is hydrogen; Y2 is hydrogen and wherein:
Y1 is C1-C10 alkyl, preferably C1-C6 alkyl, more preferably C1-C4 alkyl, most preferably methyl, ethyl, propyl, isopropyl or butyl; imidazolyl or pyridyl; mono- or di-C1-C3 alkylamino, more preferably dimethylamino or monoisopropylamino; phenyl; or C1-C10 alkyl, preferably C1-C6 alkyl, more preferably C1-C2 alkyl substituted by C1-C2 alkoxy, or phenyl and wherein,
R3 is selected from: C4-C10 straight or branched chain alkyl, preferably C5-C7 alkyl, more preferably hexyl, preferably straight chain alkyl; or;
C1-C10 alkyl, preferably C1-C4 alkyl, more preferably C2-C3 alkyl substituted by: C5-C6 cycloalkyl, preferably cyclohexyl, optionally substituted by one or more C1-C4 alkyl groups, preferably methyl or dimethyl; C3-C4 alkoxy, preferably butoxy; C5-C6 cycloalkyloxy, preferably cyclohexyloxy; aryloxy, preferably phenoxy, optionally mono-substituted at the ortho position by chlorine, or, at the ortho or para positions for fluorine, bromine, iodine, or at the o-position for C1-C2 alkyl, preferably methyl; aryl(C1-C2)alkoxy, preferably benzyloxy; C5-C6 cycloalkanoyl, preferably cyclohexanoyl; saturated 5- or 6-membered heterocyclic ring wherein the heteroatom(s) are at the 2- or 4-positions, preferably a 2-tetrahydropyranyl; or heteroaryl selected from isoxazolyl or indolyl; or;
C1-C10 alkyl, preferably C1-C3 alkyl substituted by: aryl, preferably phenyl optionally substituted by C1-C4 alkyl, preferably ortho or meta methyl or ortho or para ethyl or ortho or para mono- or di-halo, preferably chloro of fluoro, or CH2CN; ZNR4R5 wherein Z is carbonyl or a direct link, R4 is hydrogen and R5 is C5-C6 cycloalkyl, preferably, cyclohexyl; or
C2-C10 alkyl, preferably C2-C3 alkyl substituted by hydroxy and C5-C6 cycloalkyl, preferably 3-cyclohexyl-3-hydroxypropyl; or
C3-C10alkenyl, preferably, C3-C6 alkenyl, more preferably hex-5-enyl; or C3-C4 alkenyl substituted by: C5-C6 cycloalkyl, preferably cyclohexyl; aryl, preferably phenyl; or
C3-C10 alkynyl, preferably C3-C6 alkynyl, more preferably hex-2-ynyl.
Preferred Y1 groups for use herein include: methane, ethane, propane, 1-methylethane, butane, 3-pyridine, 1-methyl-1H-imidazol-4-yl, N-isopropylamino, 2-methoxyethane, N,N-dimethylamino, benzene and xcex1-toluene.
More preferred Y1 groups for use herein are: methane, ethane, propane, 1-methylethane, butane, 3-pyridine, 1-methyl-1H-imidazol-4-yl, N-isopropylamino and 2-methoxyethane.
Preferred R3 groups for use herein include: N-(N-cyclohexylamino carbonylmethyl), N-(3-(4,4-dimethylcyclohexyl)propyl), N-(2-butoxyethyl), N-(3-phenoxypropyl), N-(3-(4-fluorophenoxy)propyl), N-(2-(2-chlorophenoxy)ethyl), N-(2-cyclohexyloxyethyl), N-(2-(4-fluorophenoxy)ethyl), N-(2-(2-chlorophenyl)ethyl), N-(1-(4-cyanomethylphenyl)methyl), N-(2-phenylethyl), N-(2-(5-[2,3-dihydro-1-benzofuranyl])ethyl), N-(3-(2,6-dimethylphenoxy)propyl), N-(2-(3-indolyl)ethyl), N-(hex-5-enyl), N-(hex-2-ynyl), N-(2-(2-methylphenoxy)ethyl), N-(2-benzyloxyethyl), N-(2-cycloheyxlideneethyl), N-hexyl, N-(5-methylhexyl), N-(3-cyclohexylpropyl), N-benzyl, N-(3-phenylpropyl), N-(3-cyclohexyl-3-oxopropyl), N-(2-(3-methylphenyl)ethyl), N-(1-(4-ethylphenyl)methyl), N-(2-(2-methylphenyl)ethyl), N-(3-(2-methylphenyl)propyl), N-(3-(tetrahydropyran-2-yl)propyl), N-((S)-3-cyclohexyl-3-hydroxypropyl), N-((E)-3-cyclohexylprop-2-enyl) and N-cinnamyl.
More preferred R3 groups for use herein are: N-(2-(2-methylphenoxy)ethyl), N-(2-benzyloxyethyl), N-(2-cycloheyxlideneethyl), N-hexyl, N-(5-methylhexyl), N-(3-cyclohexylpropyl), N-benzyl, N-(3-phenylpropyl), N-(3-cyclohexyl-3-oxopropyl), N-(2-(3-methylphenyl)ethyl), N-(1-(4-ethylphenyl)methyl), N-(2-(2-methylphenyl)ethyl), N-(3-(2-methylphenyl)propyl), N-(3-(tetrahydropyran-2-yl)propyl), N-((S)-3-cyclohexyl-3-hydroxypropyl), N-((E)-3-cyclohexylprop-2-enyl) and N-cinnamyl.
Highly preferred herein are compounds wherein N(Y2)(WY1) is in the meta position, y is zero, n is zero, W=SO2, R1 and R2 are methyl groups with trans relative stereochemistry; Y2 is hydrogen and wherein Y1 is methane, ethane, propane, 1-methylethane, butane, 3-pyridine, 1-methyl-1H-imidazol-4-yl or N-isopropylamino and wherein R3 is selected from: hexyl; methyl-hexyl, preferably 5-methyhexyl; or ethyl or propyl substituted by: cyclohexyl; cyclohexanoyl; 2-tetrahydropyranyl or methyl, ethyl or propyl, substituted by: phenyl, optionally substituted by methyl or ethyl; or 3-cyclohexyl-3-hydroxypropyl; or prop-2-enyl substituted by cyclohexyl or phenyl.
Highly preferred Y1 groups for use herein are: methane, ethane, propane, 1-methylethane, butane, 3-pyridine, 1-methyl-1H-imidazol-4-yl and N-isopropylamino.
Highly preferred R3 groups for use herein are: N-hexyl, N-(5-methylhexyl), N-(3-cyclohexylpropyl), N-benzyl, N-(3-phenylpropyl), N-(3-cyclohexyl-3-oxopropyl), N-(2-(3-methylphenyl)ethyl), N-(1-(4-ethylphenyl)methyl), N-(2-(2-methylphenyl)ethyl), N-(3-(2-methylphenyl)propyl), N-(3-(tetrahydropyran-2-yl)propyl), N-((S)-3-cyclohexyl-3-hydroxypropyl), N-((E)-3-cyclohexylprop-2-enyl) and N-cinnamyl.
Highly preferred compounds according to the present invention include:
(xc2x1)-4-(3-ethanesulfonylaminophenyl)-N-hexyl-trans-3,4-dimethylpiperidine,
(xc2x1)-4-(3-ethanesulfonylaminophenyl)-N-hexyl-trans-3,4-dimethylpiperidine,
(xc2x1)-4-(3-ethanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(5-methylhexyl)piperidine,
(xc2x1)-trans-3,4-dimethyl-N-(5-methylhexyl)-4-(3-propanesulfonylaminophenyl)piperidine,
(xc2x1)-N-hexyl-trans-3,4-dimethyl-4-(3-propanesulfonylaminophenyl)piperidine,
(xc2x1)-N-(3-cyclohexylpropyl)-trans-3,4-dimethyl-4-(3-propanesulfonylaminophenyl)piperidine,
(xc2x1)-N-benzyl-trans-3,4-dimethyl-4-(3-propanesulfonylaminophenyl)piperidine,
(xc2x1)-trans-3,4-dimethyl-N-(3-phenylpropyl)-4-(3-propanesulfonylaminophenyl)piperidine,
(xc2x1)-N-hexyl-trans-3,4-dimethyl-4-(3-(2-methylethane)sulfonylaminophenyl)piperidine,
(xc2x1)-4-(3-n-butanesulfonylaminophenyl)-N-hexyl-trans-3,4-dimethylpiperidine,
(xc2x1)-N-hexyl-trans-3,4-dimethyl-4-(3-(3-pyridinesulfonylamino) phenyl)piperidine,
(xc2x1)-trans-3,4-dimethyl-N-(5-methylhexyl)-4-(3-(1-methyl-1H-imidazole-4-sulfonylamino)phenyl)piperidine,
(xc2x1)-N-hexyl-trans-3,4-dimethyl-4-(3-(1-methyl-1H-imidazole-4-sulfonylamino)phenyl)piperidine,
(xc2x1)-N-(3-cyclohexylpropyl)-trans-3,4-dimethyl-4-(3-(1-methyl-1H-imidazole-4-sulfonylamino)phenyl)piperidine,
(xc2x1)-trans-3,4-dimethyl-4-(3-(1-methyl-1H-imidazole-4-sulfonylamino) phenyl)-N-(3-phenylpropyl)piperidine,
(xc2x1)-N-hexyl-trans-3,4-dimethyl-4-(3-N-isopropylsulfamoylaminophenyl)piperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(5-methylhexyl)piperidine,
(+)-N-hexyl-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethylpiperidine,
(xc2x1)-N-(3-cyclohexyl-3-oxopropyl)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethylpiperidine,
(xc2x1)-N-(3-cyclohexylpropyl)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethylpiperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(2-(3-methylphenyl)ethyl)piperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(3-phenylpropyl)piperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(1-(4-ethylphenyl)methyl)piperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(2-(2-methylphenyl)ethyl)piperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(3-(2-methylphenyl)propyl)piperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(3-(tetrahydropyran-2-yl)-propyl)piperidine,
(xc2x1)-N-((S)-3-cyclohexyl-3-hydroxypropyl)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethylpiperidine,
(xc2x1)-N-((E)-3-cyclohexylprop-2-enyl)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethylpiperidine and
(xc2x1)-N-cinnamyl-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethylpiperidine.
Especially preferred herein are compounds wherein N(Y2)(WY1) is in the meta position, y is zero, n is zero, W=SO2, R1 and R2 are methyl groups with trans relative stereochemistry; Y2 is hydrogen and wherein Y1 is methane, ethane, propane and wherein R3 is selected from: hexyl or 5-methylhexyl; or methyl or ethyl substituted by phenyl, substituted methyl or ethyl; or propyl substituted by phenyl, optionally substituted by methyl.
Especially preferred Y1 groups for use herein are: methane, ethane and propane.
Especially preferred R3 groups for use herein are: N-hexyl, N-(5-methylhexyl), N-benzyl, N-(3-phenylpropyl), N-(2-(3-methylphenyl)ethyl), N-(2-(2-methylphenyl)ethyl) and N-(3-(2-methylphenyl)propyl).
Especially preferred compounds herein are:
(xc2x1)-4-(3-ethanesulfonylaminophenyl)-N-hexyl-trans-3,4-dimethylpiperidine,
(+)-4-(3-ethanesulfonylaminophenyl)-N-hexyl-trans-3,4-dimethylpiperidine,
(xc2x1)-4-(3-ethanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(5-methylhexyl)piperidine,
(xc2x1)-trans-3,4-dimethyl-N-(5-methylhexyl)-4-(3-propanesulfonylaminophenyl)piperidine,
(xc2x1)-N-hexyl-trans-3,4-dimethyl-4-(3-propanesulfonylaminophenyl)piperidine,
(xc2x1)-N-benzyl-trans-3,4-dimethyl-4-(3-propanesulfonylaminophenyl)piperidine,
(xc2x1)-trans-3,4-dimethyl-N-(3-phenylpropyl)-4-(3-propanesulfonylaminophenyl)piperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(5-methylhexyl)piperidine,
(+)-N-hexyl-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethylpiperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(2-(3-methylphenyl)ethyl)piperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(3-phenylpropyl)piperidine,
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(2-(2-methylphenyl)ethyl)piperidine and
(xc2x1)-4-(3-methanesulfonylaminophenyl)-trans-3,4-dimethyl-N-(3-(2-methylphenyl)propyl)piperidine.
For any of the above compounds use of a single enantiomer is preferred herein. In general, the (+) enantiomer is preferred.
According to a further aspect of the present invention there are provided compounds having the formula: 
and pharmaceutically and veterinarily acceptable salts thereof wherein:
R1 and R2 are each independently H or C1-C4 alkyl;
R3 is C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl; wherein said alkyl, alkenyl or alkynyl group may optionally be substituted by one or more substituents independently chosen from OH, ON, one or more halo atoms, amino, mono or di-(C1-C6 alkyl)amino, C1-C6 alkoxy, C2-C6 alkanoyl, C2-C6 alkanoyloxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C4-C9 cycloalkanoyl, aryl, aryloxy, aryl (C1-C4) alkoxy, heteroaryl, a saturated heterocyclic group, or adamantyl;
W is SO2, Cxe2x95x90O, P(Y1)xe2x95x90O or P(Y1)xe2x95x90S;
X is H, halo, C1-C4 alkyl, C1-C4 alkoxy, or halo (C1-C4)alkyl;
Y1 is C1-C6 alkyl which may optionally be substituted by one or more halo atoms or by OH, C1-C4 alkoxy, C2-C6 alkanoyloxy, CONH2, NH2 or aryl; NH2, mono or di-(C1-C4) alkylamino, C3-C8 cycloalkyl, aryl or heteroaryl;
Y2 is H, C1-C4 alkyl, or C2-C6 alkenyl, wherein said alkyl or alkenyl groups may optionally be substituted by aryl or heteroaryl;
and n is 0, 1 or 2.
The compounds of the invention may be prepared by a number of different processes. In one process the compounds of formula I may be prepared from an amine of the formula II: 
wherein R1, R2, R3, Y2 and n are as defined for formula (I), by reaction with a group of the formula Qxe2x80x94Wxe2x80x94Y1, wherein W and Y1 are as defined for formula I and wherein Q is a suitable leaving group and is preferably a halogen atom, generally chloro, or with an anhydride of the formula (Y1W)2O.
Thus for the preparation of the sulfonamides of formula (I) wherein W is SO2, the reaction is typically performed using a sulfonylchloride e.g. methanesulfonylchloride. The reaction is generally performed in a reaction inert organic solvent in the present of a base and is generally complete within a few hours at room temperature. The product is isolated and purified by conventional techniques.
Similarly, for the preparation of amides of formula (I) wherein W is CO, the reaction is either performed using the appropriate acylchloride or anhydride or when Y1 is C(R7)(R8)OH wherein R7 and R8 are independently selected from H, C1-C4 alkyl via rearrangement of a compound of general formula (VI) as described hereinafter, and wherein W is P(Y1)xe2x95x90O or P(Y1)xe2x95x90S, the appropriate phosphinic or thiophosphinic chloride, e.g. dimethylphosphinic chloride or dimethylphosphinothioic chloride. An alternative process proceeds via reaction of the N-unsubstituted piperidine (III): 
wherein R1, R2, Y1, Y2, W, X and n are as defined for the compound of formula (I) above, by reaction with a compound of formula R3xe2x80x94X, wherein X is chloro, bromo, iodo or a leaving group such as an arylsulfonate (e.g. bromobenzenesulfonate), and R3 is as previously defined for the compound of formula (I). The route is particularly useful when R3 is a substituted alkyl, alkenyl or alkynyl group. Thus for example reaction with an arylsubstituted bromo-alkane is achieved in a reaction inert organic solvent such as N,N-dimethylformamide in the presence of an acid acceptor such as sodium hydrogen carbonate by heating at between 80xc2x0 C. and 120xc2x0 C., preferably at about 100xc2x0 C., for 3 or 4 hours. The product is isolated and purified by conventional techniques. The route may also be adapted using an acid chloride or using an acid of formula R9CO2H with a coupling agent such as dicyclohexylcarbodiimide, to give the corresponding compound wherein the piperidine N-substituent is COR9 (where R9 is as defined for R3 but lacking a CH2 attachment group) and subsequent reduction yields the corresponding compound of formula (I).
The starting materials of formula (II) are prepared from the corresponding 3-hydroxyphenyl piperidine (IV) by conventional synthetic procedures. Thus for example the procedure shown in Scheme 1 may be used to prepare the compounds of formula II wherein R1, R2, R3 and (X)n are as defined for formula I above. 
Thus for example, when (X)n is H, and R1 and R2 are both methyl, having the trans-configuration, the process starts with (xc2x1)-4-(3-hydroxyphenyl)-trans-3,4-dimethylpiperidine. Reaction with a compound of the formula R3X, wherein X is chloro, bromo, iodo or a leaving group such as a bromobenzensulfonate group, for example hexylbromide gives the corresponding compound of formula (V). This is then reacted with caesium carbonate and sodium hydride, followed by 2-bromo-2-methylpropionamide to give the 3-(1-carbamoyl-1-methylethoxy) product (VI). Reaction of this product with sodium hydride in a reaction inert organic solvent such as N-methylpyrrolidine or N,N-dimethylformamide with heating, gives the 3-(2-hydroxy-2-methyl-propanoylamino)phenyl derivative (VIa), which is itself a compound of the invention. Subsequent hydrolysis, for example by heating with hydrochloric acid in dioxan gives the amine intermediate (II).
As an alternative process, the 3-hydroxyphenyl derivative (V) may be reacted with N-phenylbis(trifluoromethanesulfonimide) in dichloromethane in the presence of triethylamine to yield the corresponding 3-trifluoromethanesulfonyloxy derivative. This is reacted with benzophenone imine and 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl in the presence of caesium carbonate and palladium(II)acetate by heating in tetrahydrofuran, to yield the 3-diphenylmethylidineamino derivative which is subsequently treated with dilute hydrochloric acid in tetrahydrofuran to yield the 3-aminophenyl intermediate (II).
The compounds of formula (IV) are either available by literature methods or are prepared by analogous procedures from readily available starting materials. Such as, for example, preparation of the 4-methyl or 4-n-propyl substituted phenols having the general formula (IV) from 1-bromo-3-(1-methylethoxy)benzene and N-ethyl-4-piperidone as described in Preparations 43, 44 and then, either Preparations 51, 52 and the intermediate compound from Preparation 53 to provide the 4-methyl analogue or, Preparations 65 to 67 to provide the 4-n-propyl analogue herein. Also, compounds of general formula (IV) wherein (X)n is hydrogen and R1 and R3 are hydrogen or C1-C4 alkyl such as methyl or propyl and R2 is hydrogen can be made from 1-bromo-3-(1-methylethoxy)benzene and N-ethyl-4-piperidone as described in Preparations 43 to 47 herein. Compounds of general formula (V) wherein (X)n is hydrogen can be converted to compounds of general formula (V) wherein (X)n is C1-C4 alkyl such as methyl by, for example the process outlined in Preparations 71 to 73 herein. By a process analogous to that described for direct chlorination of compounds having the general formula (I), compounds of general formula (IV) wherein (X)n is hydrogen can be converted to compounds of general formula (IV) wherein (X)n is a halogen, such as chlorine by the process outlined in Examples 155 to 157.
The compounds of formula (III) are typically prepared from the corresponding compound of formula (I) wherein R3 is benzyl. This is removed by conventional catalytic hydrogenation to yield the N-unsubstituted piperidine (III).
In some cases it is possible to introduce further substituents into the compound of formula (I) directly. Such additional substituents may be obtained by conversions of the (X)n, Y1, Y2, R1 or R2 groups as described hereinafter.
Thus, for example, chlorination of a compound of the formula (I) wherein (X)n is H may be performed by reaction with a solution of chlorine in acetic acid to yield the corresponding compound where (X)n is a chlorine substituent. This process yields both the 4- and 6-substituted and the 4,6-disubstituted products.
Additional conversion of the terminal moiety of the Y1 group on compounds having the general formula (I) wherein W is SO2 and Y1 is a C1-C10 alkyl, preferably a C1-C3 alkyl group substituted by a C1-C4 alkoxy group such as for example methoxy, or, a phthalimido group, or, a C2-C6 alkanoyloxy group such as ethoxycarbonylmethane to the corresponding alcohol, alkylamine or aminocarbonyl compounds can be achieved by the methods outlined in the respective Examples 20, 18 and 22.
Conversion of the Y2 group on compounds having the general formula (I) wherein Y2 is hydrogen, to compounds wherein Y2 is an alkyl group may be achieved via direct alkylation as illustrated in Examples 69 and 78 herein.
Alternatively compounds having the general formula (I) wherein Y2 is an alkyl group can be prepared from the amine compounds having the general formula (II) wherein Y2 is hydrogen by direct alkylation of the amine to provide an alkylated amine followed by sulfonylation to provide a compound of general formula (I) as illustrated in Example 167 herein.
Similarly, compounds of formula (I) may be converted to the corresponding N-oxides via treatment with a suitable oxidising agent, such as aqueous hydrogen peroxide solution, as illustrated in Examples 168 and 169 herein.
As may be envisaged certain R3 groups having the general formula ZBNR4R5 may be converted to form different groups of the general formula ZBNR4R5, such as for example reduction of an amide of an amide group to an amine group, as illustrated hereinafter in Example 51.
The above procedures may be adapted as appropriate to the particular reactants and groups involved and other variants will be evident to the skilled chemist by reference to standard textbooks and to the examples provided hereafter to enable all of the compounds of formula (I) to be prepared.
As an alternative process, the procedure shown in Scheme 2 may be used to prepare the compounds of formula (II): 
wherein Y1, Y2, W, R1 and R2 are as defined above and wherein each Ar is a phenyl group substituted by a further group L, wherein L is a bromo, iodo or xe2x80x94NO2 or xe2x80x94OR15 group, wherein R15 is a C1-C4 alkyl group and wherein Ar is optionally substituted by one or more groups (X)n as defined above with the proviso that (X)n is not a bromo or iodo group; wherein R3 is a straight or branched chain C1-C10 alkyl group, preferably a C1-C6 alkyl group, or a benzyl group and wherein said C1-C10 alkyl group may be substituted by one or more substituents selected from: aryl, preferably phenyl; or a C3-C8 cycloalkyl group, preferably C5-C6 cycloalkyl.
In scheme 2 the starting ketone is reacted with a phosphonate compound of the general formula: (R10O)2P(O)CHR2R11 wherein R10=C1-C4 alkyl, preferably methyl or ethyl, R2 is as defined previously herein and is preferably a methyl group, R11=CO2R12 wherein R12 is a C1-C4 alkyl group, preferably ethyl, and a strong alkali metal base such as butyl lithium, sodamide, sodium hydride, sodium alkoxide and preferably potassium t-butoxide, and, a relatively inert organic solvent such as a toluene/tetrahydrofuran (THF) mixture, ether, or preferably, toluene, to provide a mixture of cis- and trans-isomers of the xcex1, xcex2 unsaturated ester compound of the general formula (VII).
The cis- and trans-isomers of compounds having the general formula (VII) can either be isolated, purified and/or separated at this stage or, as is preferred herein, isolated without purification and reduced with a suitable metal hydride reducing agent, preferably an aluminium hydride reducing agent, and especially diisobutylaluminium hydride in the presence of a suitable inert solvent such as toluene, THF, a THF/heptane mixture or preferably a THF/hexane mixture at low temperatures, in the range of from xe2x88x9278xc2x0 C. to +70xc2x0 C., preferably xe2x88x9278xc2x0 C.-+20 C., to furnish a mixture of cis- and trans-isomers of alcohols having the general formula (VIII).
These isomers of compounds having the general formula (VIII) may be separated and purified at this stage. However, it is preferred herein to isolate the isomeric mixture and react this unpurified mixture of alcohols with a compound of the formula: MeC(OR 13)3 wherein R13 is C1-C4 alkyl or aryl and is preferably methyl to give an intermediate ortho ester of general formula (VIIIa): 
which can then either be heated in the absence of solvent or, preferably heated with a suitable high boiling hydrocarbon solvent, such as xylene or preferably petroleum ether (140-160) or nonane at elevated temperatures, preferably 140xc2x0 C. to 160xc2x0 C. to provide an ester compound having the general formula (IX).
Conversion of ester compounds having the general formula (IX) to compounds of the general formula (X) is accomplished via alkaline hydrolysis with a suitable base such as lithium hydroxide, potassium hydroxide or preferably sodium hydroxide in an aqueous alcoholic solvent such as aqueous methanol, ethanol or preferably aqueous isopropyl alcohol followed by an acidic work-up. The racemic mixture of (R)- and (S)-enantiomers of acids having the general formula (X) may either be resolved at this stage, as detailed herein after, or further reacted as a racemic mixture.
Hydroboration of the double bond and concomitant reduction of the acid group followed by oxidative work up of compounds having general formula (X) provides a mixture of diols having the general formula (XI). Suitable hydroborating and reducing agents include borane/tetrahydropyran, borane/diethyl ether, borane/dioxan, borane/toluene and preferably a diborane/tetrahydofuran complex generated in situ from sodium borohydride and boron trifluoride/tetrahydofuran complex. The oxidative work-up may be performed using sodium hydroxide in the presence of hydrogen peroxide, sodium perborate or, preferably, aqueous sodium percarbonate. Separation of the diastereomeric mixture of diols having general formula (XI) may be achieved by either recrystallisation techniques or flash column chromatography on silica gel with a suitable solvent, such as ethyl acetate in toluene. The ratio of solvents utilised will be dependant upon the particular diol mixture and the silica type and such determination is within the ordinary means of the skilled chemist.
The hydroxyl groups on compounds having the general formula (XI) are activated to afford suitable leaving groups (Lxe2x80x2 and Lxe2x80x3) to provide a compound having general formula (XII) via treatment with an alkyl, or aryl sulfonylhalide or anhydride of formula R14SO2Hal wherein R14 is phenyl, 4-methylphenyl, C1-C4 alkyl, preferably ethyl or methyl, and wherein Hal is chlorine, iodine, fluorine or bromine, preferably chlorine, in the presence of one or more equivalents of an amine base such as pyridine, trimethylamine, tripropyl amine or preferably triethylamine and a suitable solvent such as dichloromethane, tetrahydrfuran, dioxan, ethyl acetate or preferably toluene or wherein Lxe2x80x2 and Lxe2x80x3 are each independently selected from a halogen such as chlorine, bromine or iodine and wherein such dihalo derivatives are formed by reaction with a suitable halogenating agent such as thionyl chloride.
Cyclisation of compound (XII) to form a compound having the general formula (XIII) is achieved via treatment with a primary amine of the formula R3NH2 wherein R3 is C1-C10 alkyl, wherein said C1-C10 alkyl may be substituted by one or more substitutents selected from: aryl, preferably phenyl; C3-C8 cycloalkyl, preferably cyclohexyl; and wherein R3NH2 is most preferably n-hexylamine. The reaction can be performed as a single phase reaction with an excess of R3NH2 in an inert organic solvent such as toluene, or, more preferably, as a 2-phase reaction system with base, which is preferably inorganic, and, optionally aqueous, such as sodium carbonate, and an inert organic solvent (other than R3NH2) such as toluene and wherein said base is preferably present at a molar equivalent level of at least 2:1 to the compound having the general formula (XII).
Conversion of compounds having the general formula (XIII) wherein L is bromo or iodo to compounds having the general formula (II) can be achieved via reaction with benzophenone imine and a suitable source of palladium such as palladium diacetate and a ligand, for the palladium, such as (R)-(+)-2,2xe2x80x2-bis(diphenyl phosphino)-1,1xe2x80x2-binaphthyl ((R)-(+)-BINAP)), or (S)-(xe2x88x92)-BINAP or a mixture of (R)-(+)- and (S)-(xe2x88x92)-BINAP in the presence of a base of formula MOR (wherein M is an alkali metal and R is a tertiary alkyl) such as sodium tertiary butoxide and a suitable solvent such as THF or toluene, or an alkali metal carbonate such as caesium carbonate in THF or dioxan as solvent. Such reaction furnishes an intermediate compound of general formula (XIV) which is treated with mineral acid, such as dilute hydrochloric acid, and optionally, heat, to provide an amine of general formula (II).
Conversion of compounds having the general formula (XIII) wherein L is xe2x80x94NO2 to compounds of the general formula (II) can be achieved either via hydrogenation with a suitable catalyst such as 10% palladium on charcoal, or, using elemental iron or iron powder and calcium chloride in aqueous ethanol.
Conversion of compounds having the general formula (XIII) wherein L is xe2x80x94OR15 wherein R15 is a C1-C4 alkyl group, preferably isopropyl to compounds of the general formula (II) can be achieved via firstly conversion to the alcohol via acidic hydrolysis followed by conversion to the trifluromethylsulfonate of the general formula (XXV) as detailed hereinbefore, and subsequent treatment with benzophenone imine, a suitable source of palladium and a ligand, followed by acid hydrolysis of the imine of general formula (XIV) to furnish a compound of general formula (II) as detailed hereinbefore.
Conversion of compounds having the general formula (II) to the desired compounds of the general formula (I) may be achieved by any of the methods detailed herein.
A preferred process wherein R1, R2 and R13 are methyl, L is bromo or iodo, Y1 is methane, ethane or propane and R3 is selected from: N-hexyl, N-(5-methylhexyl), N-benzyl, N-(3-phenylpropyl), N-(2-(3-methylphenyl)ethyl), N-(2-(2-methylphenyl)ethyl) or N-(3-(2-methylphenyl)propyl) and R12 is ethyl and (X)n is hydrogen is illustrated in Scheme 3.
The process illustrated in Scheme 3 starts with 3-bromoacetophenone, or 3-iodoacetophenone, and reaction with (EtO)2P(O)CHMeCO2Et in the presence of potassium tertiary butoxide provides the ester of formula (XV). This is then reacted with diisobutylaluminium hydride (DIBAL-H) in a tetrahydrofuran/hexane solvent mix at low temperature to provide the alcohol of formula (XVI). Reaction of this product with MeC(OMe)3 provides an intermediate product (XVII), which is generally not isolated, and which subsequently rearranges in situ while being heated at 140-160xc2x0 C. in a high boiling hydrocarbon solvent to provide compound (XVIII). Alkaline hydrolysis of this material followed by acidic work-up provides the carboxylic acid compound (XIX). Reduction of the acid group on (XIX) with concomitant hydroboration of the alkene group, preferably with borane in tetrahydrofuran, and subsequent oxidative work-up, preferably with sodium percarbonate provides diol (XX). The hydroxyl groups on diol (XX) are activated to afford suitable leaving groups (Lxe2x80x2 and Lxe2x80x3) as previously described to provide disubstituted compound (XXI). The desired product (XXI) is then refluxed with hexylamine, aqueous sodium carbonate and toluene to provide the N-hexyl 4-substituted piperidine compound (XXII). This material (XXII) is subsequently converted to an amine via, firstly, treatment with benzophenone imine, sodium tertiary butoxide, BINAP and palladium diacetate to provide the intermediate imine (XXIIa) which is subsequently converted in situ to amine (XXIII) by acid hydrolysis with aqueous hydrochloric acid. The desired material (XXIV) may then be formed either as the free base via treatment of amine (XXIII) with methane sulfonylchloride, triethylamine in toluene or as a salt via subsequent treatment with a suitable acid such as (+) or (xe2x88x92) camphor sulfonic acid. This final conversion may be carried out either at room temperature over an extended period (up to several days) or in a shorter time at elevated temperatures.
As detailed earlier herein the compounds of the invention contain one or more chiral centres and thus can exist as enantiomers and diastereoisomers. Separation of individual isomers from mixtures of isomers can occur either at the end of the process or at relevant stages throughout the process as desired by the individual chemist. Such separation may be effected using standard techniques as are known in the art.
For example, in the reaction sequences illustrated in schemes 2, 3 and 4 separation of the mixture of cis and trans geometric isomers of the compounds having the general formulae (VII), (VIII), (XV) and (XVI) during the synthesis is not necessary. However, such separation can be effected using standard chromatographic techniques.
The mixture of enantiomers having the general formula (X) or (XIX) may be resolved using a chiral amine. Suitable chiral amines include: cinchonidine, cinchonine, (S)-(xe2x88x92)-(1-naphthyl)ethyl amine, (R)-(+)-(1-naphthyl)ethyl amine or preferably (S)-(+)-cyclohexylethyl amine. The compounds are resolved via formation of a diastereomeric mixture of amine salts which can be separated via recrystallisation in a suitable solvent such as butanone, isopropanol and preferably acetone. The thus separated amine salts may then be further purified by recrystallisation and/or treated with acid, such as hydrochloric acid, to furnish the separated (+) and (xe2x88x92) forms of the acid having the general formulae (X) and (XIX). 
where the compound having the general formula (X) wherein R1 and R2 are methyl groups and L is bromine and n is zero, resolution with (S)-(+)-cyclohexylethyl amine provides the (+) compounds in a 95:5 ratio. Use of (R)-(xe2x88x92) cyclohexylethyl amine provides the (xe2x88x92) compounds in a 95:5 ratio
In the reaction sequences illustrated in schemes 2, 3 and 4 separation of the mixture of cis- and trans-diastereoisomers of the compounds having the general formulae (I), (II), (XI), (XII), (XIII), (XX), (XXI), (XXII), (XXIII) and (XXIV) wherein the enantiomeric mixture has been previously separated as detailed hereinbefore, can be achieved by either standard chromatographic techniques or recrystallisation from a suitable solvent to provide the required cis or trans compounds with a diastereomeric purity of greater than 50:50, preferably 70:30 more preferably 80:20 and most preferably 95:5. For example a diastereoisomeric mixture of compounds of the formula (XXXI), prepared from the (+) enantiomer of the compound having the general formula (XI) wherein R1 and R2 are methyl groups and L is bromine and n is zero, were separated by chromatography on silica to provide the trans-dimethyl isomer as a single (+) enantiomer in greater than 95% diastereomeric purity.
If however, no separation is carried out during the process (as described in schemes 2 to 4) then chiral phase HPLC may be used to isolate the various final compounds i.e. compounds having the general formulae (I) or (XXIV).
Preferred for use herein are trans-dimethyl isomers.
In a further alternative process, based on the procedure shown in scheme 2, the starting aryl group may have the general formula (XXV): 
wherein R15=C1-C4 alkyl, and (X)n is as defined previously herein.
This material may be converted to the corresponding ester of general formula (VII) and then to a piperidine of general formula (XIII), wherein L is xe2x80x94OR15, as detailed in schemes 2 and 3. Conversion to the alcohol via acidic hydrolysis followed by conversion to the trifluromethylsulfonate (triflate) of the general formula (XXVI) as hereinbefore detailed. 
wherein R1, R2 and R3 are as defined for the compounds of general formula (I).
Compounds having general formula (XXVI) may be converted to amines having formula (II) via the reaction with a source of palladium as detailed hereinbefore for compounds having general (XIII).
The processes illustrated herein according to the present invention for the preparation of compounds having the general formula (I) wherein the N(Y1)(WY2) group is in the meta position can be applied by analogy to prepare compounds having the general formula (I) wherein the N(Y1)(WY2) group is in the ortho or para positions.
It will be appreciated that where the processes according to the present invention for the preparation of compounds having the general formulae (I) and (XXIV) as defined herein give rise to intermediate compounds, these intermediate compounds provide additional embodiments of the invention.
Thus, according to a further aspect of the present invention there are provided intermediate compounds having the general formulae (II), (IIa), (III), (IIIa), (VI), (VIa), (VII), (VIII), (VIIIa), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIIa) and (XXIII) as illustrated in schemes 1, 2 and 3 and as described and defined hereinbefore.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention.
This may be achieved by conventional techniques, for example as described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by T W Greene and P G M Wuts, John Wiley and Sons Inc., 1991.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Further, certain compounds of formula (I) may act as prodrugs of other compounds of formula (I).
It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as xe2x80x9cpro-moietiesxe2x80x9d, for example as described in xe2x80x98Design of Prodrugsxe2x80x99 by H. Bundgaard, Elsevier, 1985, may be placed on appropriate functionalities when such functionalities are present within compounds of formula (I).
All protected derivatives, and prodrugs, of compounds of formulae (I), (II), (XXIII) and (XXIV) are included within the scope of the invention.
While it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical or veterinary formulation comprising a pharmaceutically or veterinarily acceptable carrier, diluent or excipient and a compound of the invention. Such compositions will contain from 0.1 percent by weight to 90.0 percent by weight of the active ingredient.
The methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously), or as an implant.
Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. Thus capsules, boluses or tablets may be prepared by mixing the active ingredient with a suitable finely divided diluent or carrier additionally containing a disintegrating agent and/or binder such as starch, lactose, talc or magnesium stearate, etc. Oral drenches are prepared by dissolving or suspending the active ingredient in a suitable medium. Pour-on or spot-on formulations may be prepared by dissolving the active ingredient in an acceptable liquid carrier vehicle such as butyl digol, liquid paraffin or a non-volatile ester, optionally with the addition of a volatile component such as propan-2-ol. Alternatively, pour-on, spot-on or spray formulations can be prepared by encapsulation, to leave a residue of active agent on the surface of the animal. Injectable formulations may be prepared in the form of a sterile solution which may contain other substances, for example enough salts or glucose to make the solution isotonic with blood. Acceptable liquid carriers include vegetable oils such as sesame oil, glycerides such as triacetin, esters such as benzyl benzoate, isopropyl myristrate and fatty acid derivatives of propylene glycol, as well as organic solvents such as pyrrolidin-2-one and glycerol formal. The formulations are prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.1 to 10% by weight of the active ingredient.
These formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, more usually about 5 to about 300 mg, of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discreet units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
For veterinary use, the compounds of the invention are of particular value for treating pruritus in domestic animals such as cats and dogs and in horses. Thus the invention also provides a veterinary formulation comprising a compound of the formula (I), as defined above, together with a veterinarily acceptable diluent or carrier. Such formulations include in particular tablets (including palatable tablets), ointments, pour-on formulations, spot-on formulations, dips, sprays, mousse, shampoo, collar and powder formulations. Further acceptable dosage forms include, for example, capsules, boluses or drenches.
As an alternative for treating animals, the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
For human use the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablets, capsule and ointment preparations which are formulated in accordance with standard pharmaceutical practice.
Compounds of the invention may be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms. Examples of such agents (which are provided by way of illustration and should not be construed as limiting) include antiparastics e.g. fipronil, lufenuron, imidacloprid, avermectins (e.g. abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines e.g. chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals e.g. fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials e.g. enrofloxacin, marbofloxacin, ampicillin, amoxycillin; anti-inflammatories e.g. prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements e.g. gamma-linoleic acid; and emollients.
The invention also provides for a method of treating pruritus, in a human or animal which comprises administering a therapeutically or prophylactically effective amount of a compound of the formula 1, as defined above, or a pharmaceutically or veterinarily acceptable salt thereof.
The following examples are illustrative of the preparation of typical compounds of the invention.
Melting points were determined using a Gallenkamp melting point apparatus and are uncorrected.
Nuclear magnetic resonance (NMR) spectral data were obtained using a Varian Unity 300 or 400, or Bruker AC300 or AM300 spectrometer, the observed chemical shifts (xcex4) being consistent with the proposed structures.
Mass spectral (MS) data were obtained on a Finnigan Mat. TSQ 7000, Finnigan Navigator, Fisons Instruments Trio 1000 or Micromass Platform LC spectrometer. The calculated and observed ions quoted refer to the isotopic composition of lowest mass.
HPLC means high performance liquid chromatography.
Room temperature means 20 to 25xc2x0 C.
The prepared compounds as detailed in the Examples and Preparations have been named as derivatives of 4-phenylpiperidine. IUPAC nomenclature and rules have been used to describe the substitutents thereon.
The compounds of the invention are evaluated for their activity as antipruritic agents by measuring their ability to inhibit the hind leg scratching behaviour induced in rats by the administration of a known pruritogenic agent. These studies are based on the procedure described by Berendsen and Broekkamp in the European Journal of Pharmacology,1991, 194, 201. The test is performed as follows:
Male Wistar rats (approximately 150 g body weight) are challenged with a pruritogen by subcutaneous injection of 5-methoxytryptamine hydrochloride (4 mg/3 ml/kg) dissolved in physiological saline into the scruff of the neck. At this dose a constant and quantifiable hindleg scratching response lasting up to 90 minutes is obtained.
The test compound is administered to the test animals by subcutaneous injection in an aqueous micelle formulation. The test compound is prepared in the following manner. The compound is dissolved in a vehicle (composition v/v %: glycerol formal, 24; tween 80, 17; benzyl alcohol, 1.5 and purified water to 100) then seven parts purified water is added to three parts of the above vehicle to give the aqueous micelle formulation. The compounds can be administered pre- or post-challenge or may be administered at the same time as the pruritogenic challenge.
After the pruritogen challenge has been administered, hindleg scratching is scored for each animal by recording the presence or absence of scratching during each 30 second interval as 1 or 0 scored respectively. The score for each animal is totalled after 25 minutes (maximum score 50). The efficacy of compounds is assessed by their ability to significantly reduce the score in treated groups compared to the control group.
Compounds according to the present invention, for example the compound of Example 101, were found to display anti-pruritic activity when tested in accordance with the above procedure.
Antipruritic activity was also demonstrated in dogs suffering from flea induced pruritus. Administration by subcutaneous injection or gavage at dose levels of 1-10 mg/kg led to a rapid and sustained reduction in pruritic behaviour such as scratching, rubbing and licking.